Identification of aspirin analogues that repress NF-κB signalling and demonstrate anti-proliferative activity towards colorectal cancer in vitro and in vivo

Substantial evidence indicates that aspirin and related non-steroidal anti-inflammatory drugs (NSAIDs) have potential as chemopreventative/therapeutic agents. However, these agents cannot be universally recommended for prevention purposes due to their potential side-effect profiles. Here, we compared the growth inhibitory and mechanistic activity of aspirin to two novel analogues, diaspirin (DiA) and fumaryl diaspirin (F-DiA). We found that the aspirin analogues inhibited cell proliferation and induced apoptosis of colorectal cancer cells at significantly lower doses than aspirin. Similar to aspirin, we found that an early response to the analogues was a reduction in levels of cyclin D1 and stimulation of the NF-κB pathway. This stimulation was associated with a significant reduction in basal levels of NF-κB transcriptional activity, in keeping with previous data for aspirin. However, in contrast to aspirin, DiA and F-DiA activity was not associated with nucleolar accumulation of RelA. For all assays, F-DiA had a more rapid and significant effect than DiA, identifying this agent as particularly active against colorectal cancer. Using a syngeneic colorectal tumour model in mice, we found that, while both agents significantly inhibited tumour growth in vivo, this effect was particularly pronounced for F-DiA. These data identify two compounds that are active against colorectal cancer in vitro and in vivo. They also identify a potential mechanism of action of these agents and shed light on the chemical structures that may be important for the antitumour effects of aspirin.

Cardiocentric neurophysiology:the persistence of a delusion

Aristotle is well known to have taught that the brain was a mere coolant apparatus for overheated blood and to have located the hegemonikon in the heart. This teaching was hotly disputed by his immediate successors in the Alexandrian Museum, who showed that the brain played the central role in psychophysiology. This was accepted and developed by the last great biomedical figure of classical antiquity - Claudius Galen. However, Aristotle's cardiocentric theory did not entirely disappear and this article traces its influence through the Arabic physicians of the Islamic ascendancy, into the European Middle Ages where Albertus Magnus' attempt to reconcile cardiocentric and cerebrocentric physiology was particularly influential. It shows how cardiocentricity was sufficiently accepted to attract the attention of, and require refutation by, many of the great names of the Renaissance, including Vesalius, Fernel, and Descartes, and was still taken seriously by luminaries such as William Harvey in the mid-seventeenth century. The article, in rehearsing this history, shows the difficulty of separating the first-person perspective of introspective psychology and the third-person perspective of natural science. It also outlines an interesting case of conflict between philosophy and physiology. © 2013 Copyright Taylor & Francis Group, LLC.